Recent reports identified hippocampal area CA2 as the center of a new hippocampal synaptic circuit essential for social learning, linked to autism and schizophrenia. Unlike the classic dentate gyrus-CA3-CA1 hippocampal circuit, little is known about area CA2. New reports of CA2's role in social learning provide a compelling link between this brain region and these psychiatric diseases. Therefore, understanding signaling proteins and mechanisms in hippocampal neurons is key to understanding their roles in human neuro-pathophysiology. We reported that RGS14 is highly enriched in CA2 pyramidal neurons of adult mouse, monkey and humans. We reported that RGS14 is a scaffolding protein that integrates Gi, ERK, and Ca++ signaling pathways essential for synaptic plasticity. Moreover, we discovered that RGS14 is critically important as a natural suppressor of synaptic plasticity in CA2 neurons but not CA1. RGS14-KO mice exhibit a marked and unexpected reinstatement of long-term potentiation (LTP) in CA2 neurons paired with an enhancement of hippocampal- based learning and memory, with no differences in other behaviors. RGS14 also blocks LTP in CA1 neurons when introduced, indicating it engages signaling pathways common to both CA2 and CA1 neurons. These findings highlight the importance of understanding cellular mechanism(s) whereby RGS14 regulates synaptic plasticity in hippocampal neurons. While most of what we know about RGS14 relates to regulation of postsynaptic signaling (Gi, ERK and Ca++) at dendritic spines, we also found that RGS14 localizes to various subcellular compartments including the nucleus. Within monkey brain, we show a subpopulation of native RGS14 localizes to the nuclei of neurons. Consistent with this, RGS14 contains both a nuclear localization sequence (NLS) and export sequence (NES) that enables it to shuttle in-out of the nucleus. Remarkably, we identified rare human variants of RGS14 (L504Q, R507Q) that alter the NES site resulting in RGS14 accumulation in the nucleus. This observation, along with the fact that RGS14 is a natural nucleo-cytoplasmic shuttling protein, beg the question: what is RGS14 doing in the nuclei of neurons? Our studies here show that native RGS14 localizes to the nuclei of host cells in close proximity to open DNA and active RNA Polymerase II. Based on this, we hypothesize that RGS14 serves a key role in the nuclei of hippocampal neurons, possibly as a synapse- to-nucleus co-regulator of transcribed genes important for synaptic plasticity. Therefore, the goals of these exploratory studies are to: AIM 1: Determine the effects of RGS14 and nuclear localizing human variants of RGS14 on synaptic plasticity in hippocampal neurons. AIM 2: Identify RGS14 binding partners and their signaling roles in the nuclei of hippocampal neurons. AIM 3: Determine the effects of RGS14 and nuclear localizing RGS14 variants on gene transcription in hippocampal neurons. !